Project summary The intestinal immune system is performing the formidable task to locally contain trillions of microorganisms within the gastrointestinal tract, while at the same time enabling exchange of metabolites between commensal bacteria and the intestinal epithelium. Several mechanisms have evolved to facilitate this crosstalk, including mucus secretion, antimicrobial peptide expression, and antibody production. We propose to investigate a new group of proteins involved in the maintenance of host-microbiota mutualism in the gastrointestinal tract: amyloids. Amyloid-forming proteins have so far primarily received attention in the context of the brain, where their aggregation is associated with the progression of Alzheimer?s disease. However, despite their centrality in Alzheimer?s and other neurodegenerative diseases, their primary and physiological function in neurons, and especially their function in other cell types and tissues outside of the brain, remains poorly understood. We will use a combination of tools from the fields of mucosal immunology, host-microbiome interactions, and neuroscience to identify the microbial regulators, cell type-specificity, and physiological role of amyloid proteins in the gastrointestinal tract. We hypothesize that these proteins may have a so far uncharacterized function in the regulation of intestinal host-microbiome interactions which is conserved across vertebrate species. We will systematically explore this hypothesis by using mouse models for intestinal disease, gnotobiotic strategies, and microbiota cultures, in order to delineate the upstream metabolite inducers and downstream effector mechanisms of intestinal amyloid-forming proteins. By highlighting the functional importance and Alzheimer?s disease relevance of amyloid proteins outside of the brain, this proposal will shed new light on the evolutionary role and physiological function of a group of molecules that has so far mostly been considered in a pathological context. It also represents an unconventional approach to the study of Alzheimer?s disease. Identifying microbiome-dependent pathways regulating amyloid formation in the intestine may prove highly informative for our understanding of the processes that lead to amyloid dysregulation in the brain and provide new insights in the etiology of Alzheimer?s disease. As such, this study will be the first to use an evolution-motivated, function-first and multi-tissue approach in the study of amyloids, which may serve as a blueprint for the cross-fertilization of concepts derived from distinct branches of research on different organ systems.